The objective of the proposed research is to define the potentially modifying effects of specific genetic polymorphisms that are known to be associated with neurobehavioral deficits in adults, on the neurotoxic effects of elemental mercury (Hg0) exposure from dental amalgam fillings in children. Of particular interest is a single nucleotide polymorphism (SNP) in exon 4 of the gene encoding the heme biosynthetic pathway enzyme, coproporphyrinogen oxidase (CPOX4), which both increases sensitivity to the neurobehavioral effects of Hg0 in adults and atypically modifies urinary porphyrin excretion as a potential biomarker of this effect. Of additional interest are polymorphisms of genes associated with neurotransmitter transport and function (BDNF, 5- HTTLPR, COMT, TDO2) that are reported to confer neurological deficits similar to those affected by Hg0 exposure. The long-term goal is to reduce or prevent neurological deficits potentially caused by Hg0 exposure by identifying genetic factors that may alter susceptibility to Hg toxicity and by defining the potential efficacy of an established biomarker of Hg0 exposure in susceptible children. The specific aims of the proposed analyses are to define the potential effects of the CPOX4 polymorphism on the association between Hg0 exposure and neurobehavioral performance deficits in children, and to determine if an atypical porphyrinogenic response to Hg0 exposure that is observed in adult subjects with CPOX4 also serves as a biomarker of increased susceptibility to Hg toxicity in children. An additional aim is to define potential effects of polymorphisms in other genes that are known to affect neurologic function in adults on the association between Hg0 exposure and neurobehavioral performance in children. These statistical analyses will utilize already-collected longitudinal data that include neurobehavioral test results, urinary mercury levels, cumulative Hg0 exposure indices, and urinary porphyrin measurements obtained annually from approximately300 children who participated in a randomized clinical trial between ages 8 and 18, and who have subsequently been genotyped for the polymorphisms of interest. Knowledge gained from these analyses may define genetic factors that account for differential susceptibility in boys and girls to mercury toxicity throughout the period from childhood through adolescent development. This study addresses a long-term public health goal aimed at stratifying risk to chemical toxicity based on gene- environment interactions, an approach to risk characterization that is of particular importance for children. Additionally, these findings could serve as the basis for more comprehensive studies examining the interaction of multiple genetic variants and related biochemical pathways involved in defining susceptibility to Hg0 neurotoxicity in children. PUBLIC HEALTH RELEVANCE: Exposure to elemental mercury (Hgo) poses a high risk of toxicity to children, especially those who may be particularly vulnerable to impairment of the developing central nervous system (CNS) along with attendant cognitive, personality, motor function and behavioral disorders because of genetic predisposition. The proposed study utilizes a longitudinal dataset to evaluate potential effects of several relatively common genetic polymorphisms that are known to alter neurobehavioral functions in adults on susceptibility to the neurotoxicity of Hgo in children over a period of development from childhood through late adolescence. This study addresses the long-term public health goal of improving health risk assessment in children through strategies that consider genetic susceptibility to health risks associated with exposure to Hgo and other environmental toxicants.